Osteopetrosis

Osteopetrosis (malignant)
File:Osteopetrosis pelvis X-ray.png X-ray of the pelvis of a patient with osteopetrosis, adult onset form (Albers-Schönberg disease). Note the dense bones.
Classification and external resources
Specialty
ICD-10	Q78.2
ICD-9-CM	756.52
OMIM	166600 259700
DiseasesDB	9377
eMedicine	med/1692
Patient UK	Osteopetrosis
MeSH	D010022

Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schönberg disease, is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.

It can cause osteosclerosis. The cause of the disease is understood to be malfunctioning osteoclasts. Radiological findings will show a bone-in-bone appearance.

Signs and symptoms

File:Osteopetrosis tarda2.PNG

A 17-year-old male with osteopetrosis tarda: Typical cranial deformity and thoracic scoliosis

Despite this excess bone formation, people with osteopetrosis tend to have bones that are more brittle than normal. Mild osteopetrosis may cause no symptoms, and present no problems. However, serious forms can result in stunted growth, deformity, and increased likelihood of fractures; also, patients suffer anemia, recurrent infections, and hepatosplenomegaly due to bone expansion leading to bone marrow narrowing and extramedullary hematopoiesis. It can also result in blindness, facial paralysis, and deafness, due to the increased pressure put on the nerves by the extra bone.

Comparison of bone pathology

Condition	Calcium	Phosphate	Alkaline phosphatase	Parathyroid hormone	Comments
Osteopenia	unaffected	unaffected	normal	unaffected	decreased bone mass
Osteopetrosis	unaffected	unaffected	elevated	unaffected	thick dense bones also known as marble bone
Osteomalacia and rickets	decreased	decreased	elevated	elevated	soft bones
Osteitis fibrosa cystica	elevated	decreased	elevated	elevated	brown tumors
Paget's disease of bone	unaffected	unaffected	variable (depending on stage of disease)	unaffected	abnormal bone architecture

Pathogenesis

Normal bone growth is achieved by a balance between bone formation by osteoblasts and bone resorption (breakdown of bone matrix) by osteoclasts. In osteopetrosis, the number of osteoclasts may be reduced, normal, or increased. Most importantly, osteoclast dysfunction mediates the pathogenesis of this disease.

Osteopetrosis is caused by underlying mutations that interfere with the acidification of the osteoclast resorption pit, for example due to a deficiency of the carbonic anhydrase enzyme encoded by the CA2 gene. Carbonic anhydrase is required by osteoclasts for proton production. Without this enzyme hydrogen ion pumping is inhibited and bone resorption by osteoclasts is defective, as an acidic environment is needed to dissociate calcium hydroxyapatite from the bone matrix. As bone resorption fails while bone formation continues, excessive bone is formed.

Variations

The several forms are:

Name	OMIM	Gene
OPTA1	607634	LRP5
OPTA2	166600	CLCN7
OPTB1	259700	TCIRG1
OPTB2	259710	TNFSF11
OPTB3	259730	CA2 (renal tubular acidosis)
OPTB4	611490	CLCN7
OPTB5	259720	OSTM1
OPTB6	611497	PLEKHM1
OPTB7	612301	TNFRSF11A

Differential diagnosis

The differential diagnoses include other disorders which can cause diffuse osteosclerosis, such as hypervitaminosis D and hypoparathyroidism, Paget's disease, diffuse bone metastasis of breast or prostate cancer (which tend to be osteoblastic, while most metastases are osteolytic), intoxication with fluoride, lead or beryllium, and hematological disorders such as myelofibrosis, sickle cell disease, and leukemia.

Treatment

The only durable cure for osteopetrosis types affecting the osteoclasts (most types) is bone marrow transplant.

If complications occur in children, patients can be treated with vitamin D. Gamma interferon has also been shown to be effective, and it can be associated to vitamin D. Erythropoetin has been used to treat any associated anemia. Corticosteroids may alleviate both the anemia and stimulate bone resorption. Fractures and osteomyelitis can be treated as usual.

Prevalence

There is 1 diseased for 100—200 thousands of newborns, but the chance to be diseased is greater in russian regions Chuvashia (1 diseased for 3500—4000 newborns) and Mari El (1 diseased for 14000 newborns) due to ethnogeny features of chuvash people and mari people.

Notable cases

• Laurel Burch
• Lil Bub

See also

• V-ATPase

External links

• Osteopetrosis - Pediatric Blood and Marrow Transplantation Center at University of Minnesota Masonic Children's Hospital
• GeneReviews/NCBI/NIH/UW entry on CLCN7-Related Osteopetrosis
• Rarediseases.org